Hiroaki Seino

A comparison of the handling and accuracy of syringe and vial versus prefilled insulin pen (FlexPen).

BACKGROUND To determine the preferable method for self-injecting insulin, we compared the handling, safety, and dose accuracy of a conventional disposable syringe and vial with FlexPen (Novo Nordisk A/S, Bagsvaerd, Denmark), a prefilled pen. METHODS Insulin therapy-naive healthcare professionals (HCPs) (n = 30), unfamiliar with insulin delivery, injected 10 U of insulin into a sponge pad using either a syringe and vial or the FlexPen, both with 30-gauge 8-mm needles, on day 1. The following day, they used the alternative method. They evaluated the handling of the two methods on device-specific questionnaires and compared overall preference on a third questionnaire. To evaluate dose accuracy, 30 insulin therapy-experienced HCPs and 20 insulin therapy-naive HCPs were asked to deliver 10 U of insulin using each method, and the amount discharged was weighed. RESULTS FlexPen was rated easier to use and overall more preferable than the syringe and vial by insulin therapy-naive HCPs (P < 0.001). The pen device was more accurate than the syringe and vial when used by experienced HCPs (mean +/- SD dose delivered, 9.91 +/- 0.11 U vs. 9.82 +/- 0.25 U, respectively; P < 0.001) and by insulin therapy-naive HCPs (9.91 +/- 0.12 U vs. 9.74 +/- 0.85 U; P < 0.001). CONCLUSIONS Insulin therapy-naive HCPs found FlexPen easier to handle and preferable to use compared to a conventional syringe and vial. Both insulin therapy-experienced and -naive HCPs were able to deliver insulin significantly more accurately with the FlexPen than with a syringe and vial (P < 0.001).

Dosing accuracy of two insulin pre-filled pens.

ABSTRACT Objective: This study was designed to determine the dose accuracy of two commonly available insulin pre-filled pens for use in diabetes – FlexPen*, † (Novo Nordisk A/S, Bagsværd, Denmark) (FP) and SoloStar† (Sanofi-Aventis, Paris, France) (SS). Research design and methods: Dosing accuracy was tested at 5 U, 10 U and 30 U doses – three previously unused pens of both pre-filled pens were used for each dose. At the 5 U dose each pen was tested 42 times, at the 10 U dose each pen was tested 25 times and at the 30 U dose each pen was tested 9 times. The pre-filled pens were used strictly according to manufacturers’ instructions and measurements were made on a sensitive balance and corrected for the specific density of the insulin formulations used. Specified limits were based on ISO standards (±1 U for the 5 U and 10 U doses and ±1.5 U for the 30 U dose). Results: FP was more accurate for injecting 5 U, 10 U and 30 U doses (absolute mean 4.95 ± 0.19 U, 9.61 ± 0.27 U and 29.70 ± 0.34 U, respectively) than SS (absolute mean 4.86 ± 0.39 U, 9.27 ± 0.52 U and 28.73 ± 0.47 U, respectively). No doses were outside specified limits for 5 U and 30 U with FP and 1.3% of doses were outside these limits at the 10 U dose. For SS; 1.6%, 29.3% and 33.3% of doses were below the pre-specified threshold for the 5 U, 10 U and 30 U doses, respectively. Conclusions: This non-blinded comparison indicates that FP is a more accurate insulin pre-filled pen than SS at three different insulin doses. In this single-user study, FP delivered consistent and accurate doses of insulin but SS had a high frequency of under dosing. No assessment was made of user variability in this study.

Prevention of Autoimmune Diabetes with Lymphotoxin in NOD Mice

We have reported previously that chronic and systemic administration of a streptococcal preparation (OK-432), an inducer of TNF, or of recombinant hTNF prevented the development of IDDM in the two animal models of IDDM—NOD mice and BB rats. In this study, we examined the effect of LT, which is structurally and functionally related to TNF, on NOD mice with diabetes. The cumulative incidence of diabetes at 30 wk of age was 22 of 40 (55%) in nontreated female NOD mice and was 4 of 8 (50%; NS), 3 of 29 (10%; P < 0.001), and 0 of 8 (0%; P < 0.001) in female mice treated three times a week from 4 to 30 wk of age with 5, 50, or 500 U of recombinant hLT, respectively. Intensity of insulitis was slightly reduced in the long-term LT-treated mice. LT productivity by ConA-stimulated spleen cells was examined in vitro. Although no significant difference was found between NOD mice and the other mouse strains, female NOD mice were slightly but significantly (P < 0.01) lower producers of LT immunoreactivity than male NOD mice, the diabetes incidence of which is lower than that of females. The SMLR as a marker of normal immune response, which was reported to be impaired in autoimmune animals including NOD mice, was significantly lower in female than male NOD mice. However, the low SMLR in female NOD mice was significantly increased by the administration of LT, and the increase was mediated by the responder cells of the LT-treated mice. LT productivity by ConA-stimulated spleen cells was examined in vitro. Although no significant difference was found between NOD mice and the other mouse strains, female NOD mice were slightly but significantly (P < 0.01) lower producers of LT immunoreactivity than male NOD mice, the diabetes incidence of which is lower than that of females. The SMLR as a marker of normal immune response, which was reported to be impaired in autoimmune animals including NOD mice, was significantly lower in female than male NOD mice. However, the low SMLR in female NOD mice was significantly increased by the administration of LT, and the increase was mediated by the responder cells of the LT-treated mice. These results suggest that administration of LT prevented the development of IDDM in NOD mice by modulating autoimmunity.

Increased in vivo production of tumor necrosis factor after development of diabetes in nontreated, long-term diabetic BB rats

We have recently reported that chronic and systemic administration of tumor necrosis factor alpha (TNF) inhibits development of autoimmune diabetes in NOD mice and BB rats, animal models of insulin-dependent diabetes mellitus (IDDM). During these experiments, we unexpectedly found that in vivo production of TNF stimulated by a single injection of lipopolysaccharide was enhanced approximately 10 times in the long-term diabetic BB rats (P less than 0.0001), whose mean duration of diabetes with more than 16.8 mM (300 mg/dl) of nonfasting blood glucose level was 26.2 +/- 2.1 days, as compared to that in the rats of nondiabetes and in the rats at the onset of diabetes, whose mean duration of diabetes was 1.4 +/- 0.6 days. The long-term diabetic, but not short-term-diabetic, rats were also associated with increased levels of serum fructosamine/albumin (P less than 0.01) and triglyceride (P less than 0.01) and with a decreased level of serum albumin (P less than 0.01). The in vivo TNF productivity in the diabetic rats, including the short-term- and long-term-diabetic rats, was correlated positively with the level of fructosamine/albumin (P less than 0.05) and negatively with the level of serum albumin (P less than 0.05), but not with levels of blood glucose. None of these correlations were observed in nondiabetic rats. The increased LPS-induced serum TNF activity in the long-term diabetic state was observed not only in BB rats but also in NOD mice and GK rats, a model of non-IDDM, irrespective of sexes and ages, indicating that the enhancement of in vivo TNF production was a result of long-term diabetes. These findings indicate that some factor(s) associated with the long-term-diabetic state may prime macrophages in vivo to produce TNF. Further study is needed to reveal a mechanism of the enhanced TNF production and its possible relevance to various abnormalities associated with the chronic hyperglycemic state.

Patient Acceptance and Issues of Education of Two Durable Insulin Pen Devices

BACKGROUND Insulin pen devices offer patients a more convenient, accurate, and discreet mode of insulin delivery than traditional syringes and vials. This open-label, randomized, comparative crossover study assessed patient preference for two reusable pens: NovoPen 4 (Novo Nordisk A/S, Copenhagen, Denmark) and OptiClik (Sanofi-Aventis, Bridgewater NJ). METHODS Thirty-five diabetes patients with no previous experience of pen devices (mean age 56.7 years; range 17-80 years; 57% male) used both pens to deliver a 10 unit saline dose into an injection cushion. Half received guidance according to official instruction manuals, and half were given no instructions. Learning times were also measured. Participants completed a detailed questionnaire to determine their preferences. RESULTS Overall, 32 of 35 participants preferred NovoPen 4 compared with two of 35 for OptiClik (91.4% vs. 5.7% respectively, P<0.001), and one had no preference. NovoPen 4 was significantly favored over OptiClik in almost all questionnaire criteria, including safety (P<0.001), size of pen (P<0.001), appearance (P<0.001), and ease of use (P<0.001). The majority of patients were able to use NovoPen 4 without guidance (94.4%) compared with just over half for for OptiClik (55.6%, P<0.01). Learning time was also significantly faster for NovoPen 4 (62.6 s) than for OptiClik (95.8 s) (P<0.05). CONCLUSIONS Patients learned how to use both pens quickly (under 2 min), but NovoPen 4 was preferred by participants over OptiClik. Patient acceptance of a pen device may support insulin initiation, particularly in type 2 diabetes.

Assessment of quality of life in patients with type 2 diabetes mellitus before and after starting biphasic insulin aspart 30 (BIAsp 30) therapy: IMPROVE study in Japan.

Abstract Aims: To evaluate treatment satisfaction before and after starting biphasic insulin aspart 30 (BIAsp 30) therapy in patients with type 2 diabetes mellitus (T2D) in the IMPROVE study Japan using the Diabetes Medication Satisfaction (DiabMedSat) questionnaire. Methods: The DiabMedSat questionnaire assesses overall satisfaction with drug therapy for diabetes treatment in three domains: burden, efficacy and symptoms. Patients previously treated by oral anti-diabetic drugs in the IMPROVE study Japan answered the DiabMedSat questionnaires at baseline (week 0) and week 26 after starting BIAsp 30 treatment. Results: The mean scores for each domain at weeks 0 and 26, respectively, were: burden, 64.5 and 67.5 (p = 0.041); efficacy, 55.0 and 61.5 (p < 0.001); and symptoms, 70.9 and 68.1 (p = 0.049). The overall scores were 63.4 and 65.6, respectively (p = 0.079). With regard to burden, bothersome aspects were significantly improved with BIAsp 30 treatment at week 26, compared with treatment with oral anti-diabetic drugs at week 0. Major hypoglycemic episodes were very rare; most hypoglycemic events were minor and occurred during the daytime. Conclusions: The study results indicate that BIAsp 30 does not adversely affect QOL in Japanese patients at insulin initiation.

Inhibition of autoimmune diabetes in NOD mice with serum from streptococcal preparation (OK-432)-injected mice

We have recently reported that systemic and chronic administration of recombinant tumour necrosis factor alpha (TNF‐α), as well as streptococcal preparation (OK‐432), inhibits development of insulin‐dependent diabetes mellitus (IDDM) in NOD mice and BB rats, models of IDDM. In this study we examined whether serum containing endogenous TNF induced by OK‐432 injection could inhibit IDDM in NOD mice. Treatment twice a week from 4 weeks of age with OK‐432‐injected mouse serum, which contained endogenous TNF (75U), but not IL‐1, IL‐2 and interferon‐gamma (IFN‐γ) activity, reduced the intensity of insulitis and significantly inhibited the cumulative incidence of diabetes by 28 weeks of age in NOD mice, as compared with the incidence in non‐treated mice (P<0.01) and in mice treated with control serum (P<002). This inhibitory effect of the serum was diminished, although not significantly, by neutralization of serum TNF activity with anti‐mouse TNF antibody. In the mice treated with the serum from OK‐432‐injected mice, Thy‐1.2+ or CD8+ spleen cells decreased (P<0.01) and surface‐Ig+ (S‐Ig+) cells increased (P<0.05), whereas the proliferative response of spleen cells to concanavalin A (P< 0.01) and lipopolysaccharide (P<0.05) increased. The results indicate that the inhibition by OK‐432 treatment of IDDM in NOD mice was partially mediated by serum factors including endogenous TNF.

Clinical effect of combination therapy of pioglitazone and an α-glucosidase inhibitor

SUMMARY This study evaluated the efficacy of adding pioglitazone 30 mg to the therapy of patients with type 2 diabetes mellitus whose glycaemic control was poor on an α-glucosidase inhibitor (α-GI) alone or in combination with a sulphonylurea (SU). The patients (n = 20) had a HbA1c level between 7.0 and 12.0% and the fasting plasma glucose was 7.8 mmol l−1 or higher. They were treated with 30 mg pioglitazone once daily for 16 weeks. The decrease in HbA1c at week 16 of treatment was 0.8% (7.8% at baseline dropping to 7.1% at week 16; p < 0.01). An increase in leptin was observed 4 weeks after starting the post-study period (p < 0.05). Tumour necrosis factor-α (TNF-α) and body fat percentage did not show any significant alterations. Correlations between the decrease in HbA1c at week 16 and characteristic variables of patients were examined. A correlation with leptin (p = −0.5632, p < 0.05) levels was found. Five patients experienced adverse drug reactions, such as oedema, hypoglycaemia and increased creatine phosphokinase (CK), all of which were mild in severity. The addition of pioglitazone in diabetics whose glycaemic control was poor on a α-GI alone or with a α-GI and SU combination resulted in a significant decrease in HbA1c, and the treatment was well-tolerated. Our findings also suggest that leptin levels could be useful for assessing responders to pioglitazone.

Improvement of glucose tolerance with immunomodulators in type 2 diabetic animals

Cytokine-inducers prevent insulin-dependent diabetes mellitus (IDDM) in animal models. We extended this therapy to non-insulin-dependent diabetes mellitus (NIDDM), because it was reported that diabetes of KK-Ay mice, a model for NIDDM, was recovered by allogenic bone-marrow transplantation that also prevented IDDM in animal models.An i.p. or i.v. injection of streptococcal preparation (OK 432) lowered fasting blood glucose (FBG) levels and markedly improved glucose tolerance test (GTT) in KK-Ay mice for more than 32 h regardless of the glucose loading routes (oral, i.v. or i.p.), while an i.v. injection of BCG improved FBG and GTT for more than 4 wks without body weight loss. The improvement of FBG and GTT with OK-432 was brought about in other NIDDM animals, GK rats and Wistar fatty rats. Among various cytokines possibly induced by OK-432 and BCG, IL-1α, TNFα and lymphotoxin significantly improved FBG and GTT in KK-Ay mice, whereas IL-2 and IFNγ did not. There were no differences between the OK-432-treated KK-Ay mice and control in histology of the pancreas, degree of insulin-induced decrease in blood glucose levels, and muscle glycogen synthase activities. As to insulin secretion, there is a tendency that the OK-432-treatment less than 1 week did not affect insulin levels during GTT, whereas the treatment more than 2 weeks increased the insulin levels.Thus, cytokine-inducers improved FBG and glucose tolerance of NIDDM animals probably via cytokines. The results imply a role of the cytokines in glucose tolerance of NIDDM, although precise immune and metabolic mechanisms remain to be elucidated.

Comment and reply on: Dosing accuracy of two insulin pre-filled pens

The recent publication by Asakura et al. reports a smallscale laboratory experiment comparing the dosing accuracy of two insulin injection devices (FlexPen [FP], and SoloSTAR* [SS]), suggesting that FP is more accurate than SS. However, there are numerous elements that should be taken into consideration when interpreting the results and the authors’ conclusion. As part of the approval process for introducing an insulin injection device to the market, accurate dose delivery must be demonstrated. This is commonly achieved through studies that show that the device meets the requirements of a technical laboratory standard developed by the International Organization for Standardization (namely DIN EN ISO 11608-1 for pre-filled/disposable insulin pen devices). SS met the ISO requirements for dose accuracy at each dose tested under all conditions. The compliance of sanofi-aventis data with the ISO requirements is documented by the data submitted, reviewed and approved by the relevant regulatory authorities. The publication by Asakura et al., however, makes reference to the respective ISO standard by referring to the tolerance limits (i.e. 1 unit for doses dialled of 0–20 units or 5% for doses of 20 units or more), but neither the design of this laboratory study nor the evaluation of the results completely follow ISO 11608-1. Firstly, ISO 11608-1 requires a minimum of 15 pen devices to be tested in a laboratory setting repeatedly across three specified doses, for 60 single doses at each dose level. In contrast, Asakura et al. used only three pen devices at each dose level. Each pen was tested only for dispensing one specific dose instead of the whole range of doses. Furthermore, Asakura et al. did not reach the required number of 60 single doses for the highest dose chosen by the authors. With the inconsistency in the number of doses, 126 at 5 units, 75 at 10 units and 27 at 30 units, comparing the percentages of inaccurate doses is misleading. No clear rationale was provided for why additional pen devices were not tested, particularly at the 30-unit dose, to ensure equal numbers of doses tested. Secondly, each pen device should be tested repeatedly across the range of doses, to deliver doses at the minimum, middle and maximum. For SS, this translates to doses of 1, 40 and 80 units and for FP, 1, 30 and 60 units. However, in the study by Asakura et al., the accuracy of both pen devices was determined at 5, 10 and 30 units, neglecting the higher doses. Finally, when evaluating the data, all single values were measured by Asakura et al. against the defined limits for dose accuracy individually, whereas ISO 11608-1 does not evaluate the individual measurements, but rather the mean value and the standard deviation. ISO 11608-1 is a standard for design verification purposes and acknowledges the fact that, given the limited number of data points, the accuracy can only be stated with a certain confidence level. Consequently, ISO 11608-1 claims that a defined proportion has to be within the tolerance limits (97.5%) and thereby recognises that individual values may be outside the limits without affecting the overall accuracy of the device. Asakura et al. applied the limits defined in the standard, but did not follow the respective statistical process. The authors refer to a study by Bell et al. to support the suggestion that ‘dose accuracy is better at the higher doses and poorer at the lower insulin doses’. However, in that study, the authors compared the dose accuracy of split-mix versus premixed insulin delivered via vial and syringe by diabetes or healthcare professionals.